Gene therapy is a rapidly growing field, with the explosion being led by the proven safety and efficacy of adeno-associated viruses (AAV). AAV are common to nearly all (˜95%) humans and have no side effects (such as the cancers associated with retroviruses) or toxic outcomes. They permanently deliver genes to cells, and have been used safely in over 600 patients in 48 separate clinical trials, without a single serious adverse event.
For example, it has recently been shown that viruses encoding for light-sensitive proteins can sensitize specific cell types to millisecond-timescale activation and silencing in the intact brain. A number of genetically-encoded optical sensitizers have enabled neurons to be activated and silenced in vivo in a temporally-precise fashion in response to brief pulses of light (e.g., B. Chow, X. Han, X. Qian, and E. S. Boyden, Frontiers in Systems Neuroscience. Conference Abstract: Computational and systems neuroscience. doi: 10.3389/conf.neuro.10.2009.03.347 (2009); F. Zhang, L. P. Wang, M. Brauner, J. F. Liewald, K. Kay, N. Watzke, P. G. Wood, E. Bamberg, G. Nagel, A. Gottschalk, and K. Deisseroth, Nature 446 (7136), 633 (2007); E. S. Boyden, F. Zhang, E. Bamberg, G. Nagel, and K. Deisseroth, Nat Neurosci 8 (9), 1263 (2005); X. Han and E. S. Boyden, PLoS ONE 2 (3), e299 (2007); L. Luo, E. M. Callaway, and K. Svoboda, Neuron 57 (5), 634 (2008); S. Szobota, P. Gorostiza, F. Del Bene, C. Wyart, D. L. Fortin, K. D. Kolstad, O. Tulyathan, M. Volgraf, R. Numano, H. L. Aaron, E. K. Scott, R. H. Kramer, J. Flannery, H. Baier, D. Trauner, and E. Y. Isacoff, Neuron 54 (4), 535 (2007); S. Q. Lima and G. Miesenbock, Cell 121 (1), 141 (2005)). A key method by which neurons have been sensitized to light in the mammalian brain is via viruses such as AAV and lentiviruses, which can deliver genes encoding for opsins to brains of animals ranging from mice to monkeys, in a safe and enduring fashion (e.g., A. Bi, J. Cui, Y. P. Ma, E. Olshevskaya, M. Pu, A. M. Dizhoor, and Z. H. Pan, Neuron 50 (1), 23 (2006); X. Han, X. Qian, J. G. Bernstein, H.-H. Zhou, G. Talei Franzesi, P. Stern, R. T. Bronson, A. M. Graybiel, R. Desimone, and E. S. Boyden, Neuron 62 (2), 191 (2009); F. Zhang, L. P. Wang, E. S. Boyden, and K. Deisseroth, Nat Methods 3 (10), 785 (2006); T. Ishizuka, M. Kakuda, R. Araki, and H. Yawo, Neurosci Res 54 (2), 85 (2006)). Viruses allow faster turnaround time than do transgenics, especially for organisms that are not genetic model organisms such as rats and monkeys, and for opsins may enable high expression levels that may not be possible in transgenic scenarios [H. Wang, J. Peca, M. Matsuzaki, K. Matsuzaki, J. Noguchi, L. Qiu, D. Wang, F. Zhang, E. Boyden, K. Deisseroth, H. Kasai, W. C. Hall, G. Feng, and G. J. Augustine, Proc Natl Acad Sci USA 104 (19), 8143 (2007)].
Little work has been done on supporting hardware that would enable delivery of AAV vectors to multiple points in the brain. Gene therapy technologies are typically delivered to single points in the body or brain. However, injections of viruses or other gene therapy systems at single points can only label single points; increasing the volume of virus delivered is in principle possible, but is only marginally effective, and it is impossible to label cells in a complex spatial pattern (e.g., a flat disc, or a curved line) with a single-point injector. Furthermore, it is tedious, time-consuming, and error prone to perform such injections of viruses or gene therapy systems into the brain in series. For seizure silencing, or treating Parkinson's disease, or treating depression, it may be desirable to deliver genes to multiple points in a neural network, at several points along its path. Understanding how neural circuits mediate the computations that subserve sensation, thought, emotion, and action, and are corrupted in neurological and psychiatric disorders, would be greatly facilitated by a technology for rapidly targeting genes to complex 3-dimensional neural circuits, enabling fast creation of “circuit-level transgenics.”